The TRAF2-p62 axis promotes proliferation and survival of liver cancer by activating mTORC1 pathway.
The TRAF2-p62 axis promotes proliferation and survival of liver cancer by activating mTORC1 pathway.
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DOI：
10.1038/s41418-023-01164-7
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发表时间：
2023-06
影响因子：
12.4
通讯作者：
Zheng, Min
中科院分区：
文献类型：
--
作者：
Liang, Xue;Yao, Jiping;Cui, Danrui;Zheng, Weiyang;Liu, Yanning;Lou, Guohua;Ye, Bingjue;Shui, Liyan;Sun, Yi;Zhao, Yongchao;Zheng, Min
肿瘤坏死因子受体相关因子2(TRAF2)是一种双重功能蛋白，既是一种接头蛋白，又是一种泛素E3连接酶，在介导肿瘤坏死因子α-核因子κB信号通路中起着重要作用。TRAF2的异常表达在多种人类癌症中已有报道。TRAF2是否以及如何调控肝癌细胞的生长仍不清楚。本研究的目的是研究TRAF2在肝癌中的潜在失调及其生物学功能，并阐明其潜在的机制，从而使TRAF2成为一个有吸引力的肝癌靶点。在这里，我们报告了TRAF2在人类肝癌细胞系和组织中的上调，TRAF2的高表达与肝细胞癌患者的预后不良有关。蛋白质组学分析和免疫共沉淀分析表明，p62是TRAF2的一个新底物，它通过K420残基上的K63连接而受到TRAF2诱导的多泛素化。P62和TRAF2在人肝细胞癌组织中的表达水平呈显著负相关。TRAF2的缺失通过导致p62的积聚抑制了肝癌细胞在体外和体内的生长和存活，而p62的同时被敲除可以部分挽救这一积聚。在机制上，TRAF2介导的p62多泛素化通过形成p62-mTORC1-RAG复合体来激活mTORC1，从而促进mTORC1的溶酶体定位。TRAF2的缺失通过破坏p62和mTORC1复合体之间的相互作用来抑制mTORC1的活性。总之，我们的研究提供了概念验证证据，证明TRAF2是治疗肝癌的有效靶点。
TRAF2 (Tumor necrosis factor receptor-associated factor 2) is a dual function protein, acting as an adaptor protein and a ubiquitin E3 ligase, which plays an essential role in mediating the TNFα-NFκB signal pathway. Dysregulated expression of TRAF2 has been reported in a variety of human cancers. Whether and how TRAF2 regulates the growth of liver cancer cells remains elusive. The goal of this study is to investigate potential dysregulation of TRAF2 and its biological function in liver cancer, and to elucidate the underlying mechanism, leading to validation of TRAF2 as an attractive liver cancer target. Here, we reported TRAF2 is up-regulated in human liver cancer cell lines and tissues, and high TRAF2 expression is associated with a poor prognosis of HCC patients. Proteomics profiling along with Co-immunoprecipitation analysis revealed that p62 is a new substrate of TRAF2, which is subjected to TRAF2-induced polyubiquitination via the K63 linkage at the K420 residue. A strong negative correlation was found between the protein levels of p62 and TRAF2 in human HCC samples. TRAF2 depletion inhibited growth and survival of liver cancer cells both in vitro and in vivo by causing p62 accumulation, which is partially rescued by simultaneous p62 knockdown. Mechanistically, TRAF2-mediated p62 polyubiquitylation activates the mTORC1 by forming the p62-mTORC1-Rag complex, which facilitates the lysosome localization of mTORC1. TRAF2 depletion inhibited mTORC1 activity through the disruption of interaction between p62 and the mTORC1 complex. In conclusion, our study provides the proof-of-concept evidence that TRAF2 is a valid target for liver cancer.
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影响因子：
16
作者：
Linares, Juan F.;Duran, Angeles;Yajima, Tomoko;Pasparakis, Manolis;Moscat, Jorge;Diaz-Meco, Maria T.
通讯作者：
Diaz-Meco, Maria T.
影响因子：
64.5
作者：
Moscat, Jorge;Karin, Michael;Diaz-Meco, Maria T.
通讯作者：
Diaz-Meco, Maria T.
雷公藤红素诱导的 Nur77 与 TRAF2 相互作用通过促进线粒体泛素化和自噬减轻炎症
影响因子：
16
作者：
Hu M;Luo Q;Alitongbieke G;Chong S;Xu C;Xie L;Chen X;Zhang D;Zhou Y;Wang Z;Ye X;Cai L;Zhang F;Chen H;Jiang F;Fang H;Yang S;Liu J;Diaz-Meco MT;Su Y;Zhou H;Moscat J;Lin X;Zhang XK
通讯作者：
Zhang XK
影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT
DOI：
10.4049/jimmunol.1200814
发表时间：
2012-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Pérez-Chacón G;Llobet D;Pardo C;Pindado J;Choi Y;Reed JC;Zapata JM
通讯作者：
Zapata JM